Perivascular administration of metformin through 3D minichannels improved adventitia ingrowth and endothelialization for electrospinning vascular grafts

Achieving rapid endothelialization to maintain the patency of small-diameter vascular grafts remains a significant clinical challenge. Conventional surface modification strategies provide limited biochemical signals for recruiting circulating endothelial cells and fail to mitigate perivascular scarring and fibrosis. Emerging evidence underscores the critical role of regenerated adventitia in facilitating fallout endothelialization. Based on this rationale, we hypothesized that pharmacological administration around vascular grafts could promote rapid adventitia ingrowth and accelerate fallout endothelialization, therefore fabricated three-dimensional minichannel-wrapped vascular grafts loaded with collagen-lyophilized metformin sponges (DMwVGs), which facilitated sustained release of metformin (15.5% release at 72 h, sustained over 21 days) and promoted robust adventitia ingrowth. The patency rate of DMwVGs reached 83% (15/18 overall) in a rabbit carotid artery model at two weeks, significantly outperforming metformin-loaded electrospinning-only grafts (33%, 2/6). The DMwVGs facilitated the transmural growth of vascularized neo-adventitia, driving efficient fallout endothelialization. Integrated multi-omics assays revealed that DMwVGs promoted adventitia angiogenesis via activation of the MAPK pathway (2.4-fold increase) and inhibition of the NF-κB/TNF-α pathway (62% reduction). This study represents an innovative shift from passive luminal coatings to active perivascular regenerative therapy, offering a promising platform for engineering durable small-diameter vascular grafts.